The critical preliminary data for this proposal is that contrary to the accepted dogma, following exposure to endogenous immune adjuvants MyD88 delivers a negative signal to macrophages that limits tumor control by radiation therapy. We demonstrate that in poorly immunogenic tumors, macrophages are rewired following exposure to dying cancer cells such that they suppress multiple features of the tumor immune environment. This includes the ability of T cells to control residual disease, and dendritic cell maturation. The aim of this proposal is to understand the mechanisms by which this suppression occurs, identify the regulation of macrophage suppression, and use this to identify patient populations that will respond poorly to current therapies. We hypothesize that exposure to dying cells rewires macrophage signaling such that innate activation of MyD88 suppresses local tumor immunity. The specific aims of this study are to 1: Test the hypothesis that loss of MyD88 prevents NFKB driven-anti-inflammatory gene transcription and results in increased IRF3 driven IFN transcription; 2: Test the hypothesis that signaling through Mertk-mediated ?rewiring? of macrophages changes the response to adjuvants limiting immune function in the tumor environment; and 3: Test the hypothesis that MyD88 patterns of gene expression are linked to poor patient outcome. Our study design incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using a range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to identify divergent myeloid responses in vitro and in vivo. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response to innate adjuvants in patient samples.